In the main game, contestants tried to figure out the results to various 100-person survey questions (an actual example: "We asked 100 single women who are dating married men, if his wife called you and asked you to lay off, would you?"). One contestant would have to provide an actual number from 1 to 99 ("How many women said they would?"), and then the other would have to decide whether the result was higher or lower than that number. The contestants were instructed to reason out their answers, if not to help them think, then to make things more exciting for the viewers.

Whichever contestant was correct got to try to make it across a line of five playing cards by saying whether each card was higher or lower than the previous one. They could call "freeze" at any time and then could change their last card for the next one in the deck if they won the next question. A mistake by the contestant caused them to go back to where they had previously frozen, and their opponent got to play their cards.

There were four questions per regular round. The fourth was played as sudden death; the winner of the question could either play their cards to the end for a win or pass to their opponent and hope for a mistake.

It took two rounds to win the game; if each contestant won one round, the third round would be played with only three cards on the line and only three questions.

The winner got to go on to the bonus round, the Money Cards, in which the contestant was given new money to bet with, and then had to go across a line of four cards, then a line of three, and then one final card on the top line, calling each card higher or lower and betting at least $50 on the result. (The top line, the "Big Bet," required that the contestant bet at least half the amount in their bank.)

There have been three versions of "Card Sharks." The first, hosted by Jim Perry, aired in daytime on NBC from April 24, 1978, to October 23, 1981, first at 10:00 A.M. Eastern time, then moving to noon in June 1980. The theoretical maximum on the Money Cards in this version was $28,800, which was reached by one contestant.

This version occasionally featured, in addition to the 100-person poll questions, polls of 10 audience members who all represented a certain group. It was possible to earn as much as $32,000 playing the Money Cards because the dollar amounts had changed, but no one won that much.

Later in the run, another bonus game was added, this one for a car.

A new version of "Card Sharks" with different rules began in syndication in September 2001 with host Pat Bullard. The main game was backwards in that the contestants would start by calling higher or lower along a line of seven cards (both contestants playing the same cards). Then, if a contestant was incorrect, they would have to watch a video clip and guess what would happen at the end.